CN1072654C - Benzamide derivative, compsn. containing said derivative and use thereof - Google Patents
Benzamide derivative, compsn. containing said derivative and use thereof Download PDFInfo
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- CN1072654C CN1072654C CN95192524A CN95192524A CN1072654C CN 1072654 C CN1072654 C CN 1072654C CN 95192524 A CN95192524 A CN 95192524A CN 95192524 A CN95192524 A CN 95192524A CN 1072654 C CN1072654 C CN 1072654C
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/58—Nitro radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The present invention relates to a new compound of formula (I) with one of the symbols R1, R2, R3, R4 and R5 representing OH, whereas the remaining symbols represent H; to a pharmaceutical composition containing the said compound, and to the use of said compound as antiparasital, anti-bacterial, anti-fungal agent, anti viral agent.
Description
Here R
1, R
2, R
3, R
4And R
5One of them represents OH, and remaining symbolic representation H; Relate to the pharmaceutical composition that contains described compound and relate to the purposes of described compound as antiparasitic, antibacterial agent, anti-mycotic agent, antiviral agent.
Prior art
Nitrothiazole Compound P H5576 (2-(acetoxyl group)-N-(5-nitro 2-thiazolyl) benzamide) is a following formula I compound
R wherein
1=O-COCH
3
R
2=R
3=R
4=R
5=H
The preparation and the application of this compound (below be referred to as compd B-Shi II) are disclosed in US3,950,351 and disclosed other open source literature of this application people in.
At US3, in 950,351, the preparation of formula II compd B is by making following formula: compound:
With the following formula: compound prepared in reaction:
R wherein
1, R
2, R
3, R
4And R
5One of them represents OH, and remaining symbolic representation H;
And, with prior art can predict opposite, i.e. it is antibiotic that the existence of prior art prediction acyloxy is that compound possesses, parasiticide activity and effect ... necessary, discoverable type I compound now
Here R
1, R
2, R
3, R
4And R
5One of them represents OH, and remaining symbolic representation H; Though wherein do not contain acyloxy, but have outstanding parasiticide, antibacterium, antimycotic activity.Said formula I compound is for parasite, and fungi, bacterium have basically effect immediately.Find that also described compound has antiviral activity.
We also find to contain in the composition of described chemical compounds I better also contains wetting agent.Most preferred composition is the composition that wherein contains wetting agent and starch derivative.
The test that the applicant did also shows by adopting The compounds of this invention and wetting agent simultaneously, the effect of described compound strengthens greatly, and adopt such mixture may treat for example enteron aisle pathology (diarrhoea) of lower abdomen pathology, gastrointestinal tract infection, intestinal tract infections, the property transmission infection, vaginal infection and urogenital infect.
Therefore, the present invention also relates to treat the composition that lower abdomen infects, said composition contains:
★ and wetting agent
Said composition preferably also contains starch derivative.
The present invention's general introduction
R wherein
1, R
2, R
3, R
4And R
5One of them represents OH, and remaining symbolic representation H; Preferably, R
1=OH.
The present invention also relates to contain above-mentioned formula I compound, preferably R wherein
1The formula I compound (formula III) of=OH is as the pharmaceutical composition of promoting agent.
R wherein
1=OH and R
2=R
3=R
4=R
5=H
Such composition has effect substantially immediately simultaneously to parasite, fungi, bacterium, virus or the enteron aisle pathology is had basically therapeutic action immediately and have the effect or the therapeutic action of hysteresis to a certain extent.
Such composition be suitable for treating human pathology maybe can prevent Human diseases, these diseases such as parasitic infection, infectation of bacteria, fungi infestation, diarrhoea and the pathology of other enteron aisle pathology as causing by virus.
In said composition, the weight content of formula III compd A is between 0.5 and 20%, preferably between 0.5 and 10%, more preferably between 0.5 and 5%:
The present invention also relates to the application of The compounds of this invention, particularly relate to composition of the present invention, antibacterial agent, anti-mycotic agent, the purposes of antiviral agent as antiparasitic.
Composition can further contain promoting agent such as anthelmintics and antiviral agent.
Composition also can contain wetting agent and/or starch derivative and/or vehicle.
Anti-lower abdomen pathology or infection, preferably under enteron aisle or vagina condition, Orally administered composition, preferred solids composition, contain:
The ★ wetting agent, and may, but preferably contain
At least a starch derivative of ★.
The described composition in back also can contain other promoting agent, for example wormer such as febantel (febantel), praziquantel, Tramisol, Zental, Oxfendazole, moxidectin, ivermectin mycin, milbemycin etc.
The preparation of compd B and be applied in US3, open in 950,351, and US4,315,018.
The wetting agent that exists in the composition that contains formula I Compound C (as compd A) and/or compd B is preferably anion surfactant, and be preferably selected from the group that following compound is formed: sugar ester, polyoxyethylene, polyoxypropylene, the anhydrohexitol derivative, fat alkane alcohol amide, fatty amine oxide, sucrose, mannitol, Sorbitol Powder, Yelkin TTS, Polyvinylpyrolidone (PVP), fatty acid ester, the glyceryl ester of sucrose, the glyceryl ester of wood sugar, polyoxyethylene glyceride, the ester of lipid acid and fatty alcohol-polyoxyethylene ether, and the polyoxyethylene fatty acid ester of sorbitan, the polyoxyethylene carboxylate of sorbitan, the glyceryl ester polyglycerol ester, ester of alcohol polyglycerol ester and composition thereof.
Preferred suitable wetting agent is a sucrose distearate, PVP (Polyvinylpyrolidone (PVP)) etc.
The present composition preferably contains the carboxy derivatives such as the carboxymethyl starch of starch derivative, particularly starch, its sodio-derivative or its salt.
For example for the weight of promoting agent, contain 20% weight at the most in the composition, the tensio-active agent of preferred 1-10% weight and contain 20% weight at the most, the starch derivative of preferred 1-10% weight with respect to the weight of promoting agent.
The present invention also relates to Orally administered galenic (galenic) preparation antiviral and/or that lower abdomen infects, these infect as enteron aisle, vagina, genitourinary pathology or discomfort, and said galenical is made up of the nuclear that contains composition, and composition contains:
The Compound C of ★ significant quantity and/or compd A and/or compd B be as promoting agent,
The ★ wetting agent, may but preferably contain
★ starch derivative or its salt,
Said in composition the content of water be less than 25% weight, said nuclear preferably adopts film coated, such film is insoluble in the acidic medium of stomach, but in the intestines medium dissolved.
Preferred compositions in the galenical, wetting agent etc. are meant open about the present composition those in front.
The present invention also relates to composition or galenical in treatment diarrhoea, the purposes of aspects such as treatment hepatic disease.
The present invention also relates to treat down abdominal organ such as vagina or genitourinary pathology or discomfort, the ointment of recial disease, gel, creme or suppository.Ointment is preferably the form of gel, contains chemical compounds I and/or compd B, wetting agent and vehicle.
Wetting agent is meant that preferably the front is about composition and/or those listed wetting agents of galenical.
And, the present invention also relates to contain the antibacterial cpd of formula I Compound C and/or compd B and wetting agent.Such composition is that anti-aerophil and anerobe are active, therefore has very wide activity profile.
Therefore, the present invention also relates to the method for killing or prevent that bacterium from existing or growing in medium.In said method, handle bacterium or medium with antimicrobial compound of the present invention, for example by with composition sprayed to bacterium, or undertaken by carrier being immersed in the medium etc.
The present invention also relates to treat the method for the preferred people's of animal diarrhoea, wherein compositions for use contains:
The Compound C of ★ significant quantity and/or compd B be as promoting agent,
The ★ wetting agent,
The ★ starch derivative
Said composition is Orally administered.
The invention still further relates to food compositions such as food paste or yogurt, contain as sanitas
The formula I Compound C (preferred compound A) and/or the compd B of ★ significant quantity
★ may but preferably contain wetting agent, and may but preferred and wetting agent also contain simultaneously
The ★ starch derivative.
The description of figure of the present invention
The IR of Fig. 2 expression III compd A spectrum and
Fig. 3 represents the HPLC mass spectrum of III compd A.
The description of this invention
Pure formula I compound
R wherein1,R
2,R
3,R
4And R5One of them represents OH, and remaining symbolic representation H can be prepared by formula I compound:
R wherein1,R
2,R
3,R
4And R5One of them represents acyloxy, and remaining symbolic representation H.
Said compound is suspended in the lean mixture of hydrochloric acid and water, filters then the compound after processing like this and wash the compound possibility drying after washing then with water.
Preparation embodiment
The preparation of compd A
Concrete preparation embodiment is as described below:
Will be according to US3,2g2-(acetoxyl group)-N-(5-nitro-2-thiazolyl) benzamide (being PH5776) of 950,351 disclosed methods preparation, compd B is suspended in 20ml 37% hydrochloric acid soln, and medium remains on 50 ℃ of also slowly stirrings in 24 hours.
Through after the described processing, media filtration is obtained solid particulate.The particle that washes gained with water is up to PH7 and dry in 50 ℃ of stoves.
The product outward appearance of gained is yellow needle-like crystallite, and its fusing point is 254 ℃ (fusing point is measured according to the kapillary assay method on Mettler FP instrument).
Determining of structure is to analyze by percentage (content), and UV composes (see figure 1), and IR spectrum (see figure 2) and gas chromatography-mass spectrum (see figure 3) are carried out.The result of structure determination is as follows:
C10,H7,N3,O4,S1;258
Calculated value: C 46.51% H 2.71% N 16.40% S 12.40%
Measured value: 45.98% 2.63% 16.71% 12.67%
λ
max=350nm(OD=0.605)。
Test 1
The preparation of composition O
The preparation of the present composition is by the compound with PH5776 and above-mentioned preparation, and the weight content of said compound is 4% for the weight of said compound and PH5776.
Composition A1
In 100ml water, 100g Nitazoxanide (PH5776) and 10g Polyvinylpyrolidone (PVP) (wetting agent) and 5g carboxymethyl starch are mixed the mixture of vacuum-drying gained.
Described composition can be used to prepare granula subsequently, sachet, and tablet or capsule are to be suitable for cheek or Orally administered.
Composition B1, C1, D1, E1, F1, G1
Be similar to composition A1 and prepare composition, except adopting 5g and 2g Polyvinylpyrolidone (PVP), 2g and 1g carboxymethyl starch.
Provided Nitazoxanide in the composition " N " in the following table, the content (g) of Polyvinylpyrolidone (PVP) " PVP " and carboxymethyl starch " CS ".
Composition | N (g) | PVP (g) | CS (g) |
B1 | 100 | 5 | 5 |
C1 | 100 | 2 | 2 |
D1 | 100 | 5 | 2 |
E1 | 100 | 5 | 1 |
F1 | 100 | 2 | 1 |
G1 | 100 | 5 | 0 |
Composition H1, I1, J1
The preparation of compositions that contains Nitazoxanide and other promoting agent is to contain the water-bearing media of PVP and carboxymethyl starch and add Nitazoxanide and other promoting agent prepares in described medium by preparation.Drying medium makes water content be lower than 5% then.
Composition | N g | PVP g | CS g | Other promoting agent g | Water content % |
H1 | 50 | 5 | 2 | Praziquantel 50 | 2 |
I1 | 75 | 5 | 2 | Praziquantel 50 | 1 |
J1 | 75 | 5 | 2 | Praziquantel 50 | 2 |
Composition A2 is to J2
Preparation is similar to the composition of composition A1-J1.
Composition A2-J2 is different from composition A1-J1 part and only is that they contain the mixture of Nitazoxanide (PH5776-compd B) and following formula: compound A:
(in composition A1-J1, only containing Nitazoxanide)
Compd A that following table has been adopted when having provided preparation composition A2-J2 and the amount of B.
Composition | Compd A (g) | Compd B (g) |
A2-G2 | 4 | 96 |
H2 | 2 | 48 |
I2 | 3 | 72 |
J2 | 3 | 72 |
The preparation galenical
Formulation K 1
With 500g powdery Nitazoxanide and 10g Polyvinylpyrolidone (PVP), the 20g carboxymethyl starch, the 25g W-Gum, 5g Magnesium Stearate and 50g water mix, and then the mixture that obtains are made 560mg particle (particle that promptly contains the 500mg promoting agent).The granula that then diameter that obtains is about 1 centimetre is in about 50 ℃ of dryings.
By the sugar soln that sprays heat the microparticle that obtains is coated with then, sugared coating has formed a film.Formulation K 2
With 480g Nitazoxanide (PH5776) and 20g compd A pulverulent mixture and 10g Polyvinylpyrolidone (PVP), the 20g carboxymethyl starch, the 25g W-Gum, 5g Magnesium Stearate and 50g water mix, and then the mixture that obtains are made 560mg particle (particle that promptly contains the 500mg promoting agent).The granula that then diameter that obtains is about 1 centimetre is in about 50 ℃ of dryings.
By the sugar soln that sprays heat the microparticle that obtains is coated with then, sugared coating has formed a film.
Microparticle can contain one or more vehicle or other promoting agent is conspicuous, for example Microcrystalline Cellulose (Avicel
@FMC), methylcellulose gum, ethyl cellulose, carboxymethyl cellulose, hydroxy ethyl cellulose, hydroxypropylcellulose, starch etc.
Same film also can contain:
Pharmaceutically acceptable vehicle of ★ such as softening agent (plastifiant), pigment, weighting agent, wetting agent, lubricant .... or their mixture and
But the composition of ★ film former; comprising insoluble in hydrochloric acid in gastric juice but in intestines dissolved substances (polymkeric substance or non-polymer; Mierocrystalline cellulose ethanoyl phthalic ester (acetophthalate) for example, polyvinyl ethanoyl phthalic ester, Vltra tears ... .).
Test
Test 1
The first stage pharmacokinetic study carries out oral 6 volunteers of single 500mg dosage composition O.Be about 3mcg/ml by 2-(hydroxyl)-N-(5-nitro-2-thiazolyl) benzamide in the high pressure liquid chromatography measurement blood.This product is discharged without changing in urine in after treatment first 24 hours.In blood and urine, do not find (2-acetoxyl group)-N-(5-nitro-2-thiazolyl) benzamide.
The clinical study of II phase is carried out 80 patients of sum, stool examination that repeats in the post-processed and/or vaginal smear show to be taken 3-7 days for twice composition A1 every day of 500mg continuously, and it is very effective resisting following worm or bacterium etc.: Trichomonas vaginalis, entamoeba histolytica, crisp nuclear double-core amoeba (Gardia lamblia), pinworm, seemingly draw the ascarid nematode, Necator americanus, Ancylostoma duodenale, Trichuris trichiura, strongyloides intestinalis, taeniasis bovis, taeniasis suis, a wealthy strobilization nematode (Diphylobottrium latum) and short putamina are washed worm.Tolerability is good, only can be observed a spot of Upper abdominal pain on one's body about 10% patient in the course of treatment, feels sick, vomits and diarrhoea.Before treatment and after the treatment hematochemistry that carries out and hematology test shows its be not subjected to the influence of composition.
The in vitro study of Trichomonas vaginalis shows 2-(acetoxyl group)-N-(5-nitro-2-thiazolyl), and benzamide has minimum inhibition concentration 0.5-1.25mcg/ml, and 2-(hydroxyl)-N-(5-nitro-2-thiazolyl) inhibition concentration of benzamide under same test conditions is 1-1.25mcg/ml.This parasiticide activity that has shown 2-(hydroxyl)-N-(5-nitro-2-thiazolyl) benzamide is equivalent to 2-(acetoxyl group)-N-(5-nitro-2-thiazolyl) benzamide.Yet these studies show that 2-(hydroxyl)-N-(5-nitro-2-thiazolyl), and benzamide has effect substantially immediately, and 2-(acetoxyl group)-N-(5-nitro-2-thiazolyl) benzamide is not like this.
Last in vitro study shows that anti-following Gram-positive of composition and gram-negative bacteria are effectively, aerophil such as streptococcus aureus, colon bacillus, shigella sonnei, helicobacter pylori; Anerobe such as bacteroides fragilis, ulcer fusobacterium, aerogenesis Wei Rong Salmonella, vagina add the De-Nol bacterium, the dermophyte of yeast fungus such as trichophyton mentagrophytes, microsporum audouini, acrothesium floccosum and Candida albicans.Employing formula I compound
R wherein
1, R
2, R
3, R
4And R
5One of them represents OH, and remaining symbolic representation H preferably adopts compd A, even in a small amount, can improve generalformula, particularly PH5776, or the effectiveness of compd B is possible.
Test 2 and 3
In order to show the effect of the present composition, two groups of mouse (be 4-8 age in week, 18-20g is heavy) to be tested, two groups of mouse all infect with Cryptosporidium parvum.
Mice infected is suffered from chronic diarrhoea.
Before treatment, be easy to determine by stool examination whether mouse suffers from chronic diarrhoea.
Adopt the composition D1 of the disclosed Nitazoxanide in front to treat.The through port gavage treated for 1 week for the mouse that suffers from chronic diarrhoea, accepted about 0.01g Nitazoxanide (promptly about 0.6g/kg mouse) every day.
After the one week treatment, unlikelyly distinguish out which group mouse by stool examination and at first suffer from diarrhoea.
Also adopt composition D2 treatment mice infected.The through port gavage treated for 1 week for said mouse, accepted about 0.0096g Nitazoxanide and about 0.0004g formula III compd A every day.
Before one week treatment finishes, unlikelyly determine that by the ight soil analysis which group mouse at first suffers from diarrhoea.
Test 4 and 5
Preparation contains the aqueous composition (100g) of 10g promoting agent.
For the composition of the mixture that contains Nitazoxanide or Nitazoxanide (9.6g) and compd A, also can contain the 0.5g sucrose distearate in the described composition as promoting agent.
The available set compound is treated multiple parasite, worm, bacterium and fungi.
The activity of composition provides in following table:
Active | |||||
P1 | P2 | P3 | P4 | P5 | |
The crisp nuclear double-core of protozoa trichomonas vaginalis trichomonas intestinalis Entamoeba histolytica Encamoeba dispar entamoeba coli endolimax nana colon intestines basket worm amoeba giardia lamblia Bei Shi isospora | + + + + + + + + + + | + + + + + + + + + + | Do not have+/- | Do not have | + + + + + + + + + + |
Cryptosporidium parvum Bladtocystis hominis Enterocytozoon bieneusi Septata intestinalis worm pinworm roundworm Necator americanus Ancylostoma duodenale Trichuris trichiura strongyloides intestinalis Taenia saginata Taenia solium Diplacanthus nanus | + + + + + + + + + + + + + | + + + + + + + + + + + + + | Do not have+++++do not have | Do not have+++++do not have | Do not have |
P1=Nitazoxanide+sucrose distearate
P2=Nitazoxanide+compd A+sucrose distearate
The P3=Zental
The P4=Vermox
The P5=metronidazole
Active | |||||
P1 | P2 | P3 | P4 | P5 | |
Aerophil streptococcus aureus colon bacillus Protens vulgaris anerobe | + + + | + + + | Do not have | Do not have | Do not have |
The Clostridium bacteroides belongs to Peptococcus Peptostreptococcus fusiform bacilarmature fungi Candida albicans trichophyton mentagrophytes cercosphaera addisoni acrothesium floccosum | + + + + + + + + + | + + + + + + + + + | Do not have+++ | Do not have | +++++ do not have |
P1=Nitazoxanide+sucrose distearate
P2=Nitazoxanide+compd A+sucrose distearate
The P3=Zental
P4=Vermox
The P5=metronidazole
Test 5
Provide below and measure antiviral effect and toxic general method.
Measure antiviral effect and toxic laboratory method
A, the fibroblastic preparation of human foreskin
Obtain human newborn's foreskin as far as possible soon and place the minimal essential medium (MEM) 4 hours that contains vancomycin, amphotericin B, penicillin and gentamicin (with common concentration) at the postoperative of peritomizing.Remove substratum then, foreskin is cut into pieces and repeated washing up to there not being red cell.Subsequently in the CO2 couveuse under 37 ℃ of following continuously stirring, make with 0.25% trypsinase and to organize trypsinize 15 minutes.In 15 minute later stage, make tissue place drag.The supernatant liquor that will contain cell by aseptic cheese cloth (cheesecloth) is poured in the flask that contains MEM and 10% fetal bovine serum.The flask that all will contain substratum in whole trypsin acting step is positioned in the ice.Behind each adding cell, with a small amount of MEM washing cheese cloth that contains serum.All in the foreskin fragment, add fresh trypsinase at every turn.Repeat above-mentioned steps up to there not being cell.Then, the cell that will contain substratum descended centrifugal 4 minutes in 1000RPM4 ℃.Discard the liquid supernatant liquor and with cell suspension in a small amount of MEM and 10%FBS (fetal bovine serum).Then cell is placed the 25cm of suitable number
2In the tissue culture flasks.Converge and when needing trypsin acting, they are extended in the big flask gradually when cell grows to.Cell was stored on ten thousand paddy mycins and the amphotericin to the 4th generation.
B. inhibition test one HSV of cytopathic effect, HCMV, VZV.
24 hours before use, the human foreskin inoblast of the generation number of passing at the low is inoculated in the 96 hole tissue culture plate, this is with 2.5 * 10
4The cell concn of cell/ml carries out in 0.1ml minimal essential medium (MEM), is supplemented with 10% fetal bovine serum (FBS) in the substratum.Then at CO
237 ℃ cell hatched 24 hours in the couveuse.After hatching, remove substratum and to porose in (remove first row) add the 100 μ l MEM that contain 2%FBS.In first row, in triplicate hole, add 125 μ l trial drugs.Substratum is added separately in cell and the virus control hole.Then by the manual instrument transferase 12 5 μ l medicines of Cetus liquid, by serial dilution in 1: 5 first round and remaining hole.Behind the dilution medicine, in every hole, add 100 suitable μ l viruses of concentration, except in the cell control well being adds 100 μ l MEM.For HSV-1 and HSV-2 test, adoptable virus concentration is the 1000PFU/ hole.For CMZ and VZV test, the virus concentration of adding can be the 2500PFU/ hole.Then, for HSV-1 and HSV-2, with flat board at CO
2Hatched 3 days for 37 ℃ in the couveuse, VZV was hatched 10 days or hatched concerning CMV 14 days.After incubation period, the sucking-off substratum is also with 0.1% crystal violet solution dyeing 30 minutes.Remove dyestuff then and use tap water rinsing flat board up to all too much dyestuffs of flush away.Make dull and stereotyped dry 24 hours, then at Skatron Plate Reader in 620nm place reading.
C. adopt HSV-1 that semi-solid cladding process (overlay) carries out and the plaque (plaque) of HSV-2 to reduce test.
Tested preceding 2 days, and inserted HFF (human foreskin inoblast) cell in the 6 hole flat boards and at 37 ℃ of 5%CO
2With hatch under 90% humidity.In test this day, medicine is to be made of 2 times of desired concn in 2 * MEM, adopts the medicine serial dilution of 2 * MEM with 1: 5 pair of 6 concentration then.Initial concentration normally 200 μ g/ml to 0.06 μ g/ml.Used virus is diluted to required concentration to cause 20-30 plaque in every hole in containing the MEM of 10%FBS.From the hole, inhale and remove substratum, and in two holes, respectively add 0.2ml virus, simultaneously the 0.2ml substratum is added in the hole of measuring drug toxicity.Then flat board is hatched and vibrated in per 15 minutes simultaneously in 1 hour.After incubation period, 1% agarose of equivalent is added in isopyknic each drug dilution liquid.Obtaining that final drug level begins is 100 μ g/ml, is that 0.03 μ g/ml and final agarose coverture concentration are 0.5% during end.Be added to the medicine agarose mixture of 2ml volume in each hole and hatched dull and stereotyped 3 days, afterwards with 1.5% neutral red solution to cell dyeing.After 4-6 hour incubation period finishes, inhale and remove dyestuff, adopt stereoscopic microscope to amplify 10 * doubly backs plaque counting.
EC
50(50% effective concentration) expression suppresses the required concentration of pathogenic change effect 50% of virus.
IC
50(50% inhibition concentration) expression suppresses cell proliferation 50% needed concentration.
Selectivity index (S.I.)=IC
50/ EC
50
The D.VZV plaque reduces test-semi-solid cladding process
This method and the test of above-mentioned HSV plaque are basic identical, have only two differences
1, behind the adding medicine, hatched dish 10 days.
2, at the 3rd day and the 6th day, add 1ml coverture and equivalent 2 * MEM and 1% agarose in addition.
E, CMV plaque test-semi-solid cladding process
Same and the above-mentioned HSV plaque test of this method is basic identical, has only a small amount of fine distinction.Be used for initial coverture and subsequently twice obducent agarose be 0.8% but not 1%.At the 4th day and the 8th day, be to hatch trier 14 days with other 1ml coverture.
F. adopt the obducent plaque of liquid nutrient medium to reduce test
Adopt the plaque minimizing test of coverstock to be similar to the obducent test of employing agarose, the step that adds virus is identical with the plaque test of routine.The medicine regional concentration that is adopted is the MEM that contains 2%FBS.Medicine is not to be made of 2 * concentration as above-mentioned test, but is made of required concentration.Concerning HSV-1 and HSV-2 test, the antibody preparation that will be obtained by Baxter Health Care Corporaton was by dilution in 1: 500 and join in the substratum that medicine dilutes therein and go.To CMV and VZV, in coverture, do not adopt antibody.To the CMV test, added the other substratum that does not contain new drug at the 5th day and also hatched altogether 10 days.To VZV, added other substratum at the 5th day and also hatched altogether 10 days.Concerning all tests, hatching latter stage, in each hole, adding 1: 10 neutral material diluent of 2ml and hatched 6 hours.Inhale then and remove liquid and adopt stereoscopic microscope plaque counting.
The screening of G.EBV and validation test
1. viral
Two para-infectious EBV prototypes are arranged.One class can illustrate by the virus that derives in the P3HR-1 clone supernatant liquor.This class clone produces non-transfer virus, and it causes early antigen (early antigen) generation (EA) after initial infection of B clone or superinfection.Another prototype is by the explanation of B-95-8 virus.This virus makes the rope blood lymphocytes can be not dead and cause marmoset monkey tumour.Yet, even in the clone that has the EBV genomic templates, do not cause for the moment the output sexuality to dye (abortiveproductive infection) yet.The virus that adopts in our test is P3HR-1.
2. clone
Ramos be by Burkitt ' s lymph tumor deutero-but do not contain can detected EBV genomic templates unusual B clone, and be the EBNA feminine gender, obtain Ramos/AW and contain resident EBV genomic templates/cell by the Infection in Vitro of Ramos with P3HR-1.Raji is to contain that the 60EBV gene is given birth to Burkitt ' the s lymphoma cell line of group/cell and is the first-selected cell that is used to screen the antiviral activity of anti-EBV EA expression.Daudi is the low-level producer (producer) that contains 152EBV genomic templates/cell.It spontaneously expresses EBV EA in the 0.25%-0.5% cell.It is active to can be used to proof in research subsequently.These clones are expressed EA (D) by EBV, EA (R) and VCA and superinfection is reacted.System maintains in the RPMI-1640 substratum that is supplemented with 10%FCS, L-glutaminate and 100 μ g/ml gentamicins with all cells.Supplement the nutrients to culture for twice weekly and adjust cell concn to 3 * 10
5/ ml.Cell is remained on 37 ℃ use 5%CO
2Under the condition of humidifying.
3. the immunofluorescent test of monoclonal antibody
P3HR-1 bacterial strain with EBV makes cell infection, adds trial drug after absorbing (37 ℃ following 45 minutes) and having washed cell culture.In perfect medium, hatched culture 2 days so that viral group is expressed.Behind 48 hours of hatching, count the cell number of each sample and prepare smear.In the cell of hatching, add monoclonal antibody and washing then to different EA components and VCA.Fluorescein resists-mouse Ig antibody in conjunction with rabbit subsequently; To fluorescence positive cells counting on the smear.Calculating is also compared the sum of cell positive in EA or the VCA culture.
H. hyperplasia test-toxicity
Tested preceding 24 hours, with every hole 2.5 * 10 among the MEM that contains 10%FBS
4The concentration of cell is inoculated in a 6-porose disc.Testing that day, in containing the MEM of 10%FBS, dilute medicine serially, the medicine scope is carried out with 1: 5 increment from 100 μ g/ml to 0.03 μ g/ml.For must be in DMSO the medicine of solubilising, in control wells, add the MEM that contains 10%DMSO.From the hole, inhale each drug level that removes substratum and in each hole, add 2ml more then.Then at CO
2Couveuse was hatched 72 hours in 37 ℃.During end, remove substratum-drug solution and washed cell.In each hole, add the trypsinase of lml 0.25% and hatch in dish and begin to occur cell.Inhale kinetocyte-substratum mixture tempestuously up and down with dispersion suspension liquid with suction pipe then, be added to the 0.2ml mixture in the 9.8ml Isoton III and adopt the Coulter rolling counters forward.Each sample is three parts of multiple holes, counts three times for every part.
I. Cytotoxic MTT test
Tested preceding 24 hours, with every hole 2.5 * 10
4The concentration of individual cell places 96 porose discs with the HFF cell.After 24 hours, inhale and to remove substratum and in first round, to add 125 microlitre medicines, adopt automatic Cetus liquid Handling system to dilute according to testing similar mode then serially by 1: 5 with CPE.Make dish at CO then
2Hatched 7 days in 37 ℃ in the couveuse.At this moment the solution of MTT in Dulbecco ' s phosphate buffered saline that in each hole, adds 50 microlitre concentration, 1 μ g/ml.And then dish hatched 4 hours.At this moment, remove substratum and replace with the aqueous isopropanol of 100 μ l 0.04N hydrochloric acid.After the slight vibration, go up in 550nm place reading at dish reader (plate reader).
J, toluylene red absorption test-toxicity
Obtaining the step of dull and stereotyped cell and the adding of medicine tests identical with MTT.
After adding medicine, in the CO2 couveuse, flat board was hatched 7 days in 37 ℃.Inhale the DPBS solution that removes substratum/medicine and add 200 μ l/ holes, 0.01% toluylene red this moment.It was hatched in the CO2 couveuse 1 hour.Suction is removed dyestuff and is adopted the dull and stereotyped cleaning apparatus washing of Nunc.After removing the DPBS washing lotion, 50%ETOH (ethanol)/1% glacial acetic acid that adds 200 μ g/ holes is (in H
2Among the O).Rotating Plates 15 minutes and on plate reader in 550nm recording light density.
Test 5a: the antiviral activity of hbv replication in culture (Hepatites B)
In the 2.2.15 cell culture, test step simplified summary following (Korba and Milman, 1991, the Antiviral Res of anti--HBV compound.217:217)。
★ is with human liver cell (Acs etc., 1987, PNAS84:4641) inoculation and the growth fusion in 24 hole tissue culture plate of chronic generation HBV.
★ adds test compound continuous then 9 day every day.Collected in the 0th, 3,6 and 9 day in treatment
Substratum (change every day during treating) is also preserved to treat extracellular (virus particle) HBV DNA analysis.
★ dissolves 24 hours to carry out HBV gene type assay in the cell with the cell of having handled after handling the 9th day.
★ analyzes HBV DNA at integral level HBV DNA (DNA in extracellular and the cell) and hbv replication relative rate (DNA in the cell) with qualitative and quantitative manner then.
The determination step simplified summary of toxicity of compound following (Korba and Gerin have submitted to open) in the 2.2.15 cell culture
★ makes the growth of 2.2.15 cell merge and as the above-mentioned compound treatment (in 0.2ml substratum/hole) of using on the flat tissue culture plate in 96 holes.4 kinds of concentration of each compound determination are carried out in each comfortable 3 parts of culture, differ 3-10 separately doubly.
★ preserves untreated control cultures in each 96 hole flat board.On each 96 hole flat board, not celliferous hole is used for the correction of scattering of light.
★ measures toxicity by the inhibition that neutral red is absorbed, and mensuration is after handling 9 days 24 hours, by measure the 510nm place with respect to the optical density of untreated cell carry out (Finter etc., 1969, J.Med.Chem.5:419).
The antiviral activity of compd A is compared with Zalcitabine.
We find when adopting compd A, have 50% effective concentration (EC50) that suppresses the pathogenic change effect of virus and be 1.8 ± 0.1m/ml (μ g/l), and cytotoxicity concentration (concentration that suppresses 50% hyperplasia) is greater than 1000 μ g/ml.So selectivity index SI>1000/1.8 of compd A, promptly index is greater than 500.
To Zalcitabine, test-results is as follows:
EC50: 1.8±0.2μg/ml
CC50: 261±24μg/ml
Be that selectivity index SI is 261/1.8
It is promptly about 145,
As can from the test observed, the toxicity of compd A is lower than Zalcitabine, the more suitable therapeutic action that so just can obtain anti-hbv replication has less side effect simultaneously.
The antiviral activity of the anti-VZV of test 5b
The mixture of Nitazoxanide (96%) and compd A (4%) also can be used for measuring the activity of its anti-VaricellaZoster Virus (testing laboratory's bacterial strain of standard).
Discovery is that 4 μ g/ml and CC50 are 34 μ g/ml to the EC50 of the anti-Varicella Zoster of said compound Virus, and promptly the S.I. index is about 8.5.
Consider the hypotoxicity and the validity of mixture, this mixture is particularly suitable for treating the enantiopathy toxic agent such as acycloguanosine produces chemical sproof Varicella Zoster Vins.
The compounds of this invention or composition palatable clothes are for example with tablet form.
The present composition particularly contains the composition of PH5776 and/or remaining antiviral agent, and simplexvirus is had the wide spectrum effect, these viruses as:
The single dominance of 1 type bleb (SIMPLEX) virus (HSV-1, the anti-acycloguanosine of HSV);
The single dominance virus (HSV-S, the anti-acycloguanosine of HSV-2) of 2 type blebs;
Human cytomegalovirus (the anti-ganciclovir of HCMV, HCMV);
Varicella zoster virus (the anti-acycloguanosine of VZV, VZV);
EPSTEIN-BARR BIRU.SS(EBV)
Murine cytomegalovirus (MCMV).
Can contain known in the composition as being suitable for making the vehicle of oral form.
Composition preferably contains wetting agent and may contain starch derivative.
Claims (27)
2. contain the pharmaceutical composition of following formula: compound A as promoting agent:
R wherein
1Expression OH, R
2=R
3=R
4=R
5=H.
4. according to the pharmaceutical composition of claim 2 or 3, said composition also contains wetting agent.
5. according to the pharmaceutical composition of claim 4, wherein at least a wetting agent is selected from anion surfactant.
6. according to the pharmaceutical composition of claim 4, wetting agent wherein is selected from sugar ester, polyoxyethylene, polyoxypropylene, the anhydrohexitol derivative, fat alkane alcohol amide, fatty amine oxide, sucrose, mannitol, Sorbitol Powder, Yelkin TTS, Polyvinylpyrolidone (PVP), fatty acid ester, the glyceryl ester of sucrose, the glyceryl ester of wood sugar, polyoxyethylene glyceride, the ester of lipid acid and fatty alcohol-polyoxyethylene ether, and the polyoxyethylene fatty acid ester of sorbitan, the polyoxyethylene carboxylate of sorbitan, the glyceryl ester polyglycerol ester, ester of alcohol polyglycerol ester and composition thereof.
7. according to the pharmaceutical composition of claim 2 or 3, also contain starch derivative.
8. according to the pharmaceutical composition of claim 7, wherein contain carboxymethyl starch or its salt.
9. according to the composition of claim 4, wherein contain with respect to for the promoting agent weight at the most the tensio-active agent of 20% weight and for promoting agent or multiple actives weight the starch derivative of 20% weight at the most.
10. Orally administered galenical comprises the nuclear that contains composition, and described composition contains
The compd A of ★ significant quantity
R wherein
1Expression OH, R
2=R
3=R
4=R
5=H,
The ★ wetting agent and
The ★ starch derivative,
The water content of described composition is less than 25% weight.
12., wherein contain carboxymethyl starch or its salt according to the preparation of claim 10 or 11.
13. the ointment that the treatment lower abdomen infects wherein contains
The compd A of ★ significant quantity
R wherein
1Expression OH, R
2=R
3=R
4=R
5=H and
The ★ wetting agent.
15., wherein contain starch derivative according to the ointment of claim 13 or 14.
16. compd A is as the purposes of antiparasitic,
R wherein
1Expression OH, R
2=R
3=R
4=R
5=H.
20. purposes according to claim 18 or 19, wherein antibacterial agent is antibacterial medicine, and described bacterium is selected from streptococcus aureus, colon bacillus, shigella sonnei, helicobacter pylori, crisp nuclear bacterioide, ulcer fusobacterium, aerogenesis Wei Rong Salmonella, vagina and adds the De-Nol bacterium.
21. according to the purposes of claim 20, wherein antibacterial agent is activated to anti-helicobacter pylori.
22. compd A is used as the purposes of anti-mycotic agent,
R wherein
1=OH, R
2=R
3=R
4=R
5=H.
27., contain as sanitas according to the foodstuffs compositions of claim 26
The compd A of ★ significant quantity
R wherein
1Expression OH, R
2=R
3=R
4=R
5=H and
★ following formula: compound B
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US08/227,033 US5387598A (en) | 1994-04-13 | 1994-04-13 | Composition and galenic formulation suitable for combatting affections of the lower abdomen |
US08/301,407 US5578621A (en) | 1994-09-08 | 1994-09-08 | Benzamide derivatives |
US38385595A | 1995-02-06 | 1995-02-06 | |
US08/383,855 | 1995-02-06 | ||
US08/227,033 | 1995-02-06 | ||
US08/301,407 | 1995-02-06 |
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CN1145621A CN1145621A (en) | 1997-03-19 |
CN1072654C true CN1072654C (en) | 2001-10-10 |
Family
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EP (1) | EP0755386B1 (en) |
JP (1) | JP3224395B2 (en) |
KR (2) | KR100373081B1 (en) |
CN (1) | CN1072654C (en) |
AP (1) | AP645A (en) |
AT (1) | ATE218557T1 (en) |
AU (1) | AU689582B2 (en) |
BG (1) | BG62932B1 (en) |
BR (1) | BR9507371A (en) |
CA (1) | CA2187110C (en) |
CZ (1) | CZ287002B6 (en) |
DE (1) | DE69526936T2 (en) |
DK (1) | DK0755386T3 (en) |
ES (1) | ES2161201T3 (en) |
FI (1) | FI120258B (en) |
HU (1) | HUT77404A (en) |
NZ (1) | NZ284800A (en) |
OA (1) | OA10463A (en) |
PL (1) | PL186504B1 (en) |
PT (1) | PT755386E (en) |
RU (1) | RU2140915C1 (en) |
SI (1) | SI0755386T1 (en) |
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WO (1) | WO1995028393A1 (en) |
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US5968961A (en) | 1997-05-07 | 1999-10-19 | Romark Laboratories, L.C. | Pharmaceutical compositions of tizoxanide and nitazoxanide |
US5856348A (en) * | 1994-09-08 | 1999-01-05 | Romark Laboratories, L.C. | Method for treatment of trematodes with pharmaceutical compositions of tizoxanide and nitazoxanide |
CA2467321A1 (en) | 2004-05-14 | 2005-11-14 | Paul J. Santerre | Polymeric coupling agents and pharmaceutically-active polymers made therefrom |
DE602005023181D1 (en) | 2004-07-21 | 2010-10-07 | Dana Farber Cancer Inst Inc | LENTVIRUS VECTORS AND THEIR USE |
UA90864C2 (en) * | 2004-09-09 | 2010-06-10 | Ромарк Лебораториз, Л.К. | Halogenated benzamide derivatives |
DK1976516T3 (en) | 2006-01-09 | 2013-07-15 | Romark Lab Lc | TREATMENT OF VIRAL HEPATITIS |
ES2550755T3 (en) | 2007-08-03 | 2015-11-12 | Romark Laboratories, L.C. | Thiazolide compounds substituted with alkylsulfonyl |
CN105853415A (en) | 2009-05-12 | 2016-08-17 | 罗马克实验室有限公司 | Haloalkyl heteroaryl benzamide compounds |
KR20170141830A (en) | 2009-06-26 | 2017-12-26 | 로마크 레버러토리즈, 엘.씨. | Compounds and methods for treating influenza |
CA2778182C (en) * | 2009-10-22 | 2018-04-17 | Thomas Julius Borody | Novel parasite therapy |
CN104094927B (en) * | 2013-04-02 | 2016-06-01 | 兴邦(武汉)生物科技有限公司 | A kind of assistant composition processing plant |
TW201630606A (en) * | 2015-01-21 | 2016-09-01 | 諾華公司 | GALENIC formulation comprising a topical drug |
CA3087898A1 (en) | 2018-02-02 | 2019-08-08 | Ripple Therapeutics Corporation | Glass formulations comprising steroid dimers and uses thereof |
CA3176134A1 (en) | 2020-05-01 | 2021-11-04 | Ripple Therapeutics Corporation | Heterodimer compositions and methods for the treatment of ocular disorders |
CA3219500A1 (en) * | 2021-05-28 | 2022-12-01 | Theodore HENDERSON | Treatment using an antiviral compound and nitazoxanide |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3950351A (en) * | 1973-08-08 | 1976-04-13 | S.P.R.L. Phavic | New derivatives of 2-benzamido-5-nitro thiazoles |
EP0114277A1 (en) * | 1982-12-21 | 1984-08-01 | Miles Laboratories, Inc. | Carnivore anthelmintics |
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FR1306603A (en) * | 1958-08-14 | 1962-10-19 | Innothera Lab Sa | Thiazole derivatives and their preparation process |
FR716M (en) * | 1960-08-05 | 1961-08-07 | ||
FR2435905A1 (en) * | 1978-09-13 | 1980-04-11 | Anvar | Molluscicidal 2:halo benzamido 5:nitro thiazole(s) - prepd. from 2-amino 5-nitro thiazole and a halo benzoyl chloride |
US4315018A (en) * | 1978-12-07 | 1982-02-09 | Rossignol Jean F | Specific parasiticidal use of 2-benzamido-5-nitro-thiazole derivatives |
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1995
- 1995-04-11 CZ CZ19962959A patent/CZ287002B6/en not_active IP Right Cessation
- 1995-04-11 KR KR10-2000-7003874A patent/KR100373081B1/en not_active IP Right Cessation
- 1995-04-11 AU AU23440/95A patent/AU689582B2/en not_active Ceased
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- 1995-04-11 JP JP52669395A patent/JP3224395B2/en not_active Expired - Lifetime
- 1995-04-11 WO PCT/EP1995/001334 patent/WO1995028393A1/en not_active Application Discontinuation
- 1995-04-11 AT AT95917310T patent/ATE218557T1/en not_active IP Right Cessation
- 1995-04-11 ES ES95917310T patent/ES2161201T3/en not_active Expired - Lifetime
- 1995-04-11 KR KR1019960705785A patent/KR100348440B1/en not_active IP Right Cessation
- 1995-04-11 DE DE69526936T patent/DE69526936T2/en not_active Revoked
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- 1995-04-11 CN CN95192524A patent/CN1072654C/en not_active Expired - Fee Related
- 1995-04-11 PL PL95316757A patent/PL186504B1/en not_active IP Right Cessation
- 1995-04-11 HU HU9602798A patent/HUT77404A/en unknown
- 1995-04-11 CA CA002187110A patent/CA2187110C/en not_active Expired - Lifetime
- 1995-04-11 SK SK1307-96A patent/SK281949B6/en not_active IP Right Cessation
- 1995-04-11 EP EP95917310A patent/EP0755386B1/en not_active Revoked
- 1995-04-11 PT PT95917310T patent/PT755386E/en unknown
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- 1995-04-11 RU RU96119364A patent/RU2140915C1/en not_active IP Right Cessation
- 1995-04-11 AP APAP/P/1996/000866A patent/AP645A/en active
- 1995-04-11 BR BR9507371A patent/BR9507371A/en not_active IP Right Cessation
-
1996
- 1996-10-03 BG BG100884A patent/BG62932B1/en unknown
- 1996-10-04 OA OA60900A patent/OA10463A/en unknown
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3950351A (en) * | 1973-08-08 | 1976-04-13 | S.P.R.L. Phavic | New derivatives of 2-benzamido-5-nitro thiazoles |
EP0114277A1 (en) * | 1982-12-21 | 1984-08-01 | Miles Laboratories, Inc. | Carnivore anthelmintics |
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